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Synergistic and Selective Copper/ppm Pd-Catalyzed SuzukiMiyaura Couplings: In Water, Mild Conditions, with Recycling Sachin Handa, Justin D. Smith, Matthew S Hageman, Monica Gonzalez, and Bruce H. Lipshutz ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02809 • Publication Date (Web): 01 Nov 2016 Downloaded from http://pubs.acs.org on November 1, 2016
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ACS Catalysis
Synergistic and Selective Copper/ppm Pd-Catalyzed Suzuki-Miyaura Couplings: In Water, Mild Conditions, with Recycling Sachin Handa, Justin D. Smith, Matthew S. Hageman, Monica Gonzalez, and Bruce H. Lipshutz* Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106-9510, United States ABSTRACT: Copper-catalyzed Suzuki-Miyaura couplings can be carried out exclusively on aryl iodides under very mild conditions made possible by synergistic effects due to the presence of ppm levels of palladium as co-catalyst. The coupling requires a hemi-labile P(O)-N ligand, together with the benefits of micellar catalysis using water as the recyclable reaction medium KEYWORDS: copper catalysis, micellar catalysis, green chemistry, E factor, Trace-metals
According to the review scribed by Colacot, Snieckus and coworkers tracing the history of Pd-catalyzed coupling reactions leading up to the 2010 Nobel Prizes, the Suzuki-Miyaura (SM) crosscoupling ranks as the most heavily used “name” reaction of the previous decade.1 And while palladium remains today among the leading transition metals in organic synthesis,2 its use comes with a price in terms of both its cost as a precious metal, and its limited accessibility from the Earth’s upper crust, making it an endangered element.3 Fortunately, there are technologies designed for its recycling;4 however, much is lost at varying stages of use, and thus, calls for more economical and Earth-abundant alternatives continue to produce new processes that rely on base metals. Nickel, within the group 10 series, has certainly garnered its fair share of attention from synthetic chemists,5 but so has copper come into focus in this regard.6 Interestingly, like nickel, copper is also considered endangered.7 This similar categorization, however, derives from mining as the world’s primary access, and unlike palladium, copper is not effectively recycled.8 Processes based on copper, therefore, that move away from palladium usage typically in the 1-5 mol % range and yet offer recycling of the metal, and can be conducted under environmentally responsible conditions, should be of considerable potential value.
wer energy pathway. Thus, after oxidative addition of trace amounts of Pd to the aryl iodide (Ar-I), as in B, another aryl group from ligand-bound Cu (A) can transmetalate to Pd(II) intermediate B to form C, rather than the far less energetically favorable conversion of Cu(I) (A) to Cu(III) (D). Scheme 1. Plausible mechanisms for Cu/ppm Pd catalysis of SM couplings Ar
LCuIOTf LCuI Ar A
LCuII Ar Ar Ar'
LCuIII Ar' I
PdII Ar' C Ar'-PdIII B Pd 0
Ar Ar'
D
In this report, we describe a new Cu/ppm Pd technology that provides a solution to this problem; that is, selective SM reactions that can be run under the mildest and greenest conditions reported to date based on a remarkable, ligand-controlled synergistic effect between copper and ppm levels of an added palladium salt (Figure 1).
Unlike electrophile selective palladium-catalyzed SM reactions,9 copper catalysis is initiated via transmetalation by an arylboron partner, a process that tends to be very sensitive to the nature of the boron-containing nucleophile,6c,6e and thus, limits the generality of this method. Furthermore, due to air sensitivity, usually high reaction temperatures, and use of toxic (especially diploar aprotic) organic solvents, existing methods have limited practical applications. On the other hand, reliance on the preferred reactivity of aryl iodides is a particularly intriguing feature, suggesting that selective couplings in the presence of other halides, in particular aryl bromides, might be possible, thereby extending the usefulness of a copper-mediated coupling. From a mechanistic perspective (Scheme 1), after transmetalation from boron, insertion of a ligated (L) Ar-Cu(I) species (A) into an aryl iodide (Ar’-I) is energetically demanding,10 and is likely to be responsible for the high reaction temperatures needed to form a Cu(III) intermediate (D). To overcome the associated limitations, including expansion of the boron-containing partners to include aryl Bpin, boronic acids, and BF3K salts, we have found that ppm levels of palladium can play a pivotal role when in the presence of a hemi-labile ligand on copper, directing the coupling through a lo-
Figure 1. Cu/ppm Pd catalyzed selective Suzuki-Miyaura couplings.
Previous, elegant work6d-e,11 advancing the field of Cu-catalyzed SM couplings (Figure 1) have tended to involve not only organic
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solvents, such as problematic DMF, but also elevated reaction temperatures that can require extended periods of time. Additives such as alkoxides used in excess as base, and molecular iodine, are common, as is the sensitivity of these couplings, not surprisingly, to the choice of both copper salt and associated ligand. Our approach, unique to this area, is to encourage couplings to take place within nanoreactors composed of a designer surfactant that self-aggregates in water into micellar arrays of the appropriate size and shape to accommodate substrates, catalyst, and additives.12 Initially, attempts to couple aryl iodide 1 with boronic acid 2 using inexpensive Cu(OAc)2 according to Scheme 2 were totally fruitless; no reaction was observed. Screening sources of copper in the presence of different ligands led to the finding that Cu(OTf)2 together with P,N-ligand L12 (see Supporting Information) and open to air gave the biaryl product 3 in high yield. Use of CuOTf afforded similar results under these conditions. Other salts of copper, including CuI, CuBr, CuCl, and CuOAc, in air or under argon gave no coupling product.
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Table 1. Suzuki-Miyaura couplings with, or without, ppm Pd HO I
L12 (10 mol %) Cu(OTf) 2 (10 mol %)
B OH + (1.2-2.0 equiv)
Na 2CO3 (2.0 equiv), 45 oC 2 wt % TPGS-750-M/H2O
P(t-Bu) 2 L12 =
NMe 2 Cl
OBu F CF3
4 60%, 72 h *64%, 34 h
5 80% 39 h *82%, 28 h
BuO
BuO
7 81% 48 h *91%, 28 h
8 62% 24 h *65%, 20 h Br
O
F 3C
O O
9
F
10 72%, 40 h
73%, 32 h
Further study as to the role of the copper salt, in this case with triflate as the gegenion, led to the observation that using either CuOTf or Cu(OTf)2 in an inert (argon) atmosphere, under otherwise identical conditions, no coupling occurs. The requirement for oxygen in the system suggested that P,N-ligand L12 could be subject to oxidation, and that its derived phosphine oxide might play a role in this catalysis. Interestingly, attempted prior oxidation of ligand L12 in THF over time using H2O2 was unsuccessful; however, clean oxidation in the same medium could be effected within two hours by introducing an equivalent of TfOH. Running this same cross-coupling, therefore, in the presence of this pre-formed ligand L13, but now using previously inactive freshly recrystallized Cu(OAc)2, afforded the biaryl 3 in 90% yield (Scheme 3). These experiments suggest that use of a copper(I) or (II) triflate provides the ion needed to convert P,N-ligand L12 in situ to its derived P(O),N-ligand analog L13, which is the actual copper-containing catalyst in these SM couplings. They also implicate air as supplying the oxygen needed for the
6 68% 72 h *70%, 38 h CF3
OMe
Br
On the basis of these findings, and using Na2CO3 as base (2 equiv), several biaryl couplings were run to investigate the scope of this new process. Table 1 illustrates our findings, arrived at in all cases at 45 °C, which appears to be the mildest conditions yet described for such Cu-catalyzed SM couplings. Yields, in general, were found to be moderate to good, although no obvious trend surfaced as to the nature of the coupling partners. However, times to completion tended to be long, typically between 1-2 days or more, while functional group tolerance was questionable, as more complicated educts appeared to be problematic.
O
O
BuO
Scheme 2. Cu-catalyzed SM reactions.
Conditions: ArI (0.5 mmol), Ar’B(OH)2 (0.75-1.00 mmol, 1.5-2.0 equiv), L12 (0.05 mmol, 10 mol %), Cu(OTf)2 (0.05 mmol, 10 mol %), Na2CO3 (1.0 mmol, 2.0 equiv), 45 oC, 2 wt % aqueous TPGS-750M.
F
F 11 67%, 39 h *70%, 26 h
Conditions: ArI (0.5 mmol), Ar’B(OH)2 (0.75-1.00 mmol, 1.5-2.0 equiv), L12 (0.05 mmol, 10 mol %), Cu(OTf)2 (0.05 mmol, 10 mol %), Na2CO3 (1.0 mmol, 2.0 equiv), 45 oC, 1.0 mL 2 wt % aqueous TPGS-750-M. *with 200 ppm Pd(OAc)2.
conversion of L12 to its corresponding phosphine oxide, and the high temperatures and times previously recorded are needed to generate the catalyst.6d-e Both L12 and L13 are easily distinguished by NMR spectroscopy, clearly indicating the difference in chemical shift and splitting pattern between L12, L13, and L13-Cu(OTf)2 (Figure 2). Applying this new ligand, therefore, but under far milder conditions (45 °C), led to biaryl 3 in high yield. Scheme 3. Use of Cu(OAc)2 together with phosphine oxide ligand L13 OH B OH
I + MeO
1
BuO
L13-Cu(OAc) 2 (10 mol %) DIPEA or Na 2CO3 (2.0 equiv) 2 wt %TPGS-750-M/H 2O
2 OBu
O P(t-Bu)2 L13 =
MeO
3, 90%
NMe 2
Conditions: 1 (0.5 mmol), 2 (1.00 mmol, 2.0 equiv, in 3 portions at 4 h intervals), L13 (0.05 mmol, 10 mol %), Cu(OAc)2 (0.05 mmol, 10 mol %), Na2CO3 (138 mg, 1.0 mmol, 2.0 equiv), 45 oC, 12 h, 2 wt % aqueous TPGS-750-M. *with 150 ppm Pd(OAc)2.
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ACS Catalysis Given that the combination of ligand L12 and cat. Cu/ppm Pd is chemoselective for cross-couplings involving aryl iodides in water under mild conditions, the presence of an aryl bromide in either partner leads to a product that can be further utilized in the same reaction mixture. Once an initial coupling is complete, addition of our Fe/ppm Pd nanoparticles (NPs),14 or alternatively (dtbpf)PdCl2 (1 mol %), to the aqueous reaction mixture leads to a second SM coupling in very good overall yields to form products 19 and 21 (Scheme 5).
L13-Cu(OTf)2
L13
Scheme 5. Sequential, 1-pot couplings. L12
F
I
Br 17 +
F
Figure 2. Stacked NMRs of L12, L13, and L13-Cu(OTf)2
Since the preferred ligand is of the P(O),N variety (Figure 3), addition of trace amounts of palladium into the reaction mixture might lead to transient chelation of both metals within nanomicelles at high concentrations. The examples in Table 1,
KF 3B
cat. Cu/ppm Pd surf/water, 45 °C
F
cat. Fe/ppm Pd NPs surf/water, 45 °C
F
Br B(OH) 2
F
12
18
19, 75%
Br I
O-n-Bu O-n-Bu
MeO
O
20 cat. Cu/ppm Pd + O-n-Bu surf/water, 45 °C
O
B(MIDA)
(dtbpf)PdCl 2 (1 mol %) surf/water, 45 °C
MeO
Br
21, 70%
OMe B(OH) 2
14
3
Figure 3. X-ray structure of ligand L13 as its TfOH salt.
using 200 ppm Pd(OAc)2, illustrate the benefits of this additive for both reaction rates and yields in these couplings. That the presence of Pd in these nanoreactors may be enough to alter the mechanistic pathway is further supported by each of the examples shown in Scheme 4, where no product is obtained in the absence of 150 ppm Pd(OAc)2.13
Control experiments were also conducted to confirm the synergistic effects by Cu/ppm Pd. Reaction between 17 and 18 in the absence of either Cu(OTf)2 or ppm levels of Pd(OAc)2, or both, failed to afford product 12. However, introduction of (L12)Cu(OTf)2 and traces of palladium to the same pot afforded the anticipated biaryl (Scheme 6). Attempts to conduct couplings using cat. Cu/ppm Pd conditions, albeit using a traditional organic medium, did not lead to the expected biaryl product (i.e., no reaction), further highlighting the benefits of micellar catalysis in organic synthesis. Scheme 6. Control experiments confirming a synergistic effect.
Scheme 4. Products obtained only in the presence of ppm Pd. I conditions
+
Br
Br
F
B(OH) 2
17
18
F conditions
no Pd and Cu; only ligand L12
no reaction
no LCu(OTf) 2, 24 h, 150 ppm Pd(OAc) 2
